Potassium channel inhibitors

ABSTRACT

Compounds useful as potassium channel inhibitors and especially useful for the treatment of cardiac arrhythmias and cell proliferative disorders are described.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. 119 (e)(1) ofprior filed provisional applications No. 60/231,296 filed Sep. 8, 2000and No. 60/171,397 filed on Dec. 21, 1999.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention is broadly directed to a class of compoundsuseful as potassium channel inhibitors.

[0004] 2. Description of Related Art

[0005] The importance of potassium channels was first recognized almostfifty years ago when Hodgkin and Huxley discovered that potassium ionscontributed to the current that excited the squid giant axon. Researchin the area, however, was hampered by the lack of selective, highaffinity ligands for potassium channels. But the advent of recombinantDNA techniques and single cell and whole cell voltage clamp techniqueshas changed the slow pace of the field. Indeed, potassium channels whichexhibit functional, pharmacological and tissue distributioncharacteristics have been cloned. These cloned potassium channels areuseful targets in assays for identifying candidate compounds for thetreatment of various disease states. Potassium channels have turned outto be the most diverse family of ion channels discovered to date. Theymodulate a number of cellular events such as muscle contraction,neuro-endocrine secretion, frequency and duration of action potentials,electrolyte homeostasis, and resting membrane potential.

[0006] Potassium channels are expressed in eukaryotic and prokaryoticcells, and are elements in the control of electrical and nonelectricalcellular functions. Potassium channels have been classified according totheir biophysical and pharmacological characteristics. Subclasses ofthese channels have been named based on amino acid sequence andfunctional properties. Salient among these are the voltage dependentpotassium channels, for example voltage gated potassium channels (e.g.,Kv1, Kv2, Kv3, Kv4). Subtypes within these subclasses have beencharacterized as to their putative function, pharmacology anddistribution in cells and tissues (Chandy and Gutman, “Voltage-gatedpotassium channel genes” in Handbook of Receptors and Channels-Ligandand Voltage-gated Ion Channels, ed. R. A. North, 1995; Doupnik et al.,Curr. Opin. Neurobiol. 5:268, 1995). For example, the Kv1 class ofpotassium channels is further subdivided depending on the molecularsequence of the channel, for example Kv 1.1, Kv 1.3, Kv 1.5. Functionalvoltage-gated K+ channels can exist as multimeric structures formed bythe association of either identical or dissimilar subunits. Thisphenomenon is thought to account for the wide diversity of K+ channels.However, subunit compositions of native K+ channels and the physiologicrole that particular channels play are, in most cases, still unclear.

[0007] Membrane depolarization by Kv 1.3 inhibition has been shown to bean effective method to prevent T-cell proliferation and therefore hasapplications in many autoimmune conditions. Inhibition of K+ channels inthe plasma membrane of human T-lymphocytes has been postulated to play arole in eliciting immunosuppressive responses by regulatingintracellular Ca++ homeostasis, which has been found to be important inT-cell activation.

[0008] The Kv 1.3 voltage-gated potassium channel is found in neurons,blood cells, osteoclasts and T-lymphocytes. The Chandy and Cahalanlaboratories proposed a hypothesis that blocking the Kv 1.3 channelwould elicit an immunosuppressant response. (Chandy et al., J. Exp. Med.160, 369, 1984; Decoursey et al., Nature, 307, 465, 1984). However, theK+ channel blockers employed in their studies were non-selective. Untilresearch with the peptide margatoxin, a peptide found in scorpion venom,no specific inhibitor of the Kv 1.3 channel existed to test thishypothesis. Although a laboratory (Price et al, Proc. Natl. Acad. Sci.USA, 86, 10171, 1989) showed that charybdotoxin would block Kv 1.3 inhuman T cells, charybdotoxin was subsequently shown to inhibit fourdifferent K+ channels (Kv 1.3 and three distinct small conductance Ca++activated K+ channels) in human T-lymphocytes, limiting the use of thistoxin as a probe for the physiological role of Kv 1.3 (Leonard et al,Proc. Natl. Acad. Sci. USA, 89, 10094, 1992). Margatoxin, on the otherhand, blocks only Kv 1.3 in T-cells, and has immunosuppressant activityin both in vitro and in vivo models. (Lin et al., J. Exp. Med., 177,637, 1993). The therapeutic utility of this compound, however, islimited by its potent toxicity. Recently, a class of compounds has beenreported that may be an attractive alternative to the above-mentioneddrugs, see for example U.S. Pat. Nos. 5,670,504; 5,631,282; 5,696,156;5,679,705; and 5,696,156. While addressing some of the activity/toxicityproblems of previous drugs, these compounds tend to be of largemolecular weight and are generally produced by synthetic manipulation ofa natural product, isolation of which is cumbersome and labor intensive.

[0009] Immunoregulatory abnormalities have been shown to exist in a widevariety of autoimmune and chronic inflammatory diseases, includingsystemic lupus erythematosis, chronic rheumatoid arthritis, type I andII diabetes mellitus, inflammatory bowel disease, biliary cirrhosis,uveitis, multiple sclerosis and other disorders such as Crohn's disease,ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis,ichthyosis, Graves ophthalmopathy and asthma.

[0010] Although the underlying pathogenesis of each of these conditionsmay be quite different, they have in common the appearance of a varietyof auto-antibodies and self-reactive lymphocytes. Such self-reactivitymay be due, in part, to a loss of the homeostatic controls under whichthe normal immune system operates. Similarly, following a bone-marrow oran organ transplantation, the host lymphocytes recognize the foreigntissue antigens and begin to produce antibodies which lead to graftrejection.

[0011] One end result of an autoimmune or a rejection process is tissuedestruction caused by inflammatory cells and the mediators they release.Anti-inflammatory agents such as NSAID's act principally by blocking theeffect or secretion of these mediators but do nothing to modify theimmunologic basis of the disease. On the other hand, cytotoxic agents,such as cyclophosphamide, act in such a nonspecific fashion that boththe normal and autoimmune responses are shut off. Indeed, patientstreated with such nonspecific immunosuppressive agents are as likely tosuccumb from infection as they are from their autoimmune disease.

[0012] Cyclosporin A (CsA), which was approved by the US FDA in 1983 iscurrently the leading drug used to prevent rejection of transplantedorgans. In 1993, FK-506 (Prograf) was approved by the US FDA for theprevention of rejection in liver transplantation. CsA and FK-506 act byinhibiting the body's immune system from mobilizing its vast arsenal ofnatural protecting agents to reject the transplant's foreign protein. In1994, CsA was approved by the US FDA for the treatment of severepsoriasis and has been approved by European regulatory agencies for thetreatment of atopic dermatitis. Though they are effective in fightingtransplant rejection, CsA and FK-506 are known to cause severalundesirable side effects including nephrotoxicity, neurotoxicity, andgastrointestinal discomfort. Therefore, a selective immunosuppressantwithout these side effects still remains to be developed. Potassiumchannel inhibitors promise to be the solution to this problem.

[0013] Atrial fibrillation (AF) is the most common sustained cardiacarrhythmia in clinical practice and is likely to increase in prevalencewith the aging of the population. Currently, AF affects more than 1million Americans annually, represents over 5% of all admissions forcardiovascular diseases and causes more than 80,000 strokes each year inthe United States. While AF is rarely a lethal arrhythmia, it isresponsible for substantial morbidity and can lead to complications suchas the development of congestive heart failure or thromboembolism.Currently available Class I and Class III antiarrhythmic drugs reducethe rate of recurrence of AF, but are of limited use because of avariety of potentially adverse side effects including ventricularproarrhythmia. Because current therapy is inadequate and fraught withside effects, there is a clear need to develop new therapeuticapproaches.

[0014] Antiarrhythmic agents of Class III are drugs that cause aselective prolongation of the duration of the action potential withoutsignificant cardiac depression. Available drugs in this class arelimited in number. Examples such as sotalol and amiodarone have beenshown to possess interesting Class III properties (Singh B. N., VaughanWilliams E. M. “A Third Class Of Anti-Arrhythmic Action: Effects OnAtrial And Ventricular Intracellular Potentials And OtherPharmacological Actions On Cardiac Muscle, of MJ 1999 and AH 3747” Br. JPharmacol 1970; 39:675-689. and Singh B. N., Vaughan Williams E. M, “TheEffect Of Amiodarone, A New Anti-Anginal Drug, On Cardiac Muscle”, Br JPharmacol. 1970; 39:657-667.), but these are not selective Class IIIagents. Sotalol also possesses Class II effects which may cause cardiacdepression and is contraindicated in certain susceptible patients.Amiodarone, also is not a selective Class III antiarrhythmic agentbecause it possesses multiple electrophysiological actions and isseverely limited by side effects (Nademanee, K. “The AmiodaroneOdessey”. J. Am. Coll. Cardiol. 1992; 20:1063-065.) Drugs of this classare expected to be effective in preventing ventricular fibrillation.Selective class III agents, by definition, are not considered to causemyocardial depression or an induction of arrhythmias due to inhibitionof conduction of the action potential as seen with Class Iantiarrhythmic agents.

[0015] Class III agents increase myocardial refractoriness via aprolongation of cardiac action potential duration. Theoretically,prolongation of the cardiac action potential can be achieved byenhancing inward currents (i.e. Na+ or Ca2+ currents; hereinafter I_(Na)and I_(Ca), respectively) or by reducing outward repolarizing potassium(K+) currents. The delayed rectifier (IK) K+ current is the main outwardcurrent involved in the overall repolarization process during the actionpotential plateau, whereas the transient outward (I_(to)) and inwardrectifier (I_(K1)) K+ currents are responsible for the rapid initial andterminal phases of repolarization, respectively. Cellularelectrophysiologic studies have demonstrated that IK consists of twopharmacologically and kinetically distinct K+ current subtypes, IKr(rapidly activating and deactivating) and IKs (slowly activating anddeactivating)(Sanguinetti and Jurkiewicz, Two Components Of CardiacDelayed Rectifier K+ Current: Differential Sensitivity To Block By ClassIH Antiarrhythmic Agents, J Gen Physiol 1990, 96:195-215). Class IIIantiarrhythmic agents currently in development, including d-sotalol,dofetilide (UK-68,798), almokalant (H234/09), E-4031 andmethanesulfonamide-N-[I′-6-cyano-1,2,3,4-tetrahydro-2-naphthalenyl)-3,4-dihydro4-hydroxyspiro[2H-1-benzopyran-2,4′-piperidin]-6yl]monochloride, predominantly, if not exclusively, block 1Kr. Although,amiodarone is a blocker of IKs (Balser J. R. Bennett, P. B., Hondeghem,L. M. and Roden, D. M. “Suppression Of Time-Dependent Outward Current InGuinea Pig Ventricular Myocytes: Actions Of Quinidine And Amiodarone.Circ. Res. 1991, 69:519-529), it also blocks I_(Na), and I_(Ca), effectsthyroid function, is a nonspecific adrenergic blocker, and acts as aninhibitor of the enzyme phospholipase (Nademanee, K. “The AmiodaroneOdessey”. J. Am. Coll. Cardiol. 1992; 20:1063-1065). Therefore, itsmethod of treating arrhythmia is uncertain. Most Class III agents thatare known to be in development predominantly block IKr.

[0016] Reentrant excitation (reentry) has been shown to be a prominentmechanism underlying supraventricular arrhythmias in man. Reentrantexcitation requires a critical balance between slow conduction velocityand sufficiently brief refractory periods to allow for the initiationand maintenance of multiple reentry circuits to coexist simultaneouslyand sustain AF. Increasing myocardial refractoriness by prolongingaction potential duration (APD), prevents and/or terminates reentrantarrhythmias. Most selective Class III antiarrhythmic agents currently indevelopment, such as d-sotalol and dofetilide predominantly, if notexclusively, block IKr, the rapidly activating component of IK foundboth in atrium and ventricle in man.

[0017] Since these IKr blockers increase APD and refractoriness both inatria and ventricle without affecting conduction per se, theoreticallythey represent potential useful agents for the treatment of arrhythmiaslike AF. These agents have a liability in that they have an enhancedrisk of proarrhythmia at slow heart rates. For example, torsades depoints has been observed when these compounds are utilized (Roden, D. M.“Current Status of Class III Antiarrhythmic Drug Therapy”, Am J.Cardiol, 1993; 72:44B-49B). This exaggerated effect at slow heart rateshas been termed “reverse frequency-dependence”, and is in contrast tofrequency-independent or frequency-dependent actions (Hondeghem, L. M.“Development of Class III Antiarrhythmic Agents” J. Cadiovasc. Cardiol.20 (Suppl. 2):S 17-S22).

[0018] The slowly activating component of the delayed rectifier (IKs)potentially overcomes some of the limitations of IKr blockers associatedwith ventricular arrhythmias. Because of its slow activation kineticshowever, the role of IKs in atrial repolarization may be limited due tothe relatively short APD of the atrium. Consequently, although IKsblockers may provide distinct advantage in the case of ventriculararrhythmias, their ability to affect SVT is considered to be minimal.

[0019] The ultra-rapidly activating delayed rectifier K+ current(I_(kur)) is believed to represent the native counterpart to a clonedpotassium channel designated Kv1.5 and, while present in human atrium,it appears to be absent in human ventricle. Furthermore, because of itsrapidity of activation and limited slow inactivation, I_(kur) isbelieved to contribute significantly to repolarization in human atrium.Consequently, a specific blocker of I_(kur), that is a compound whichblocks Kv 1.5, would overcome the shortcoming of other compounds byprolonging refractoriness by retarding repolarization in the humanatrium without causing the delays in ventricular repolarization thatunderlie arrhythmogenic after depolarizations and acquired long QTsyndrome observed during treatment with current Class III drugs.

[0020] In intact human atrial myocytes an ultra-rapidly activatingdelayed rectifier K+ current I_(kur) which is also known as thesustained outward current, I_(sus) or I_(so), has been identified andthis current has properties and kinetics identical to those expressed bythe human K+ channel clone (hKv1.5, HK2) when isolated from human heartand stably expressed in human (HEK-293) cell lines. (Wang, Fermini andNatel, 1993, Circ Res 73:1061-1076; Fedida et al., 1993, Circ Res73:210-216; Snyders, Tamkun and Bennet, 1993, J Gen Physiol 101:513-543)and originally cloned from rat brain (Swanson et al., 10, Neuron4:929-939). Although various antiarrythmic agents are now available onthe market, those having both satisfactory efficacy and a high margin ofsafety have not been obtained. For example, antiarrythmic agents ofClass I according to the classification scheme of Vaughan-Williams(“Classification Of Antiarrhythmic Drugs” In: Cardiac Arrhythrnias,edited by: E. Sandoe, E. Flensted-Jensen, K. Olesen; Sweden, Astra,Sodertalje, pp449-472, 1981) which cause a selective inhibition of themaximum velocity of the upstroke of the action potential (max) areinadequate for preventing ventricular fibrillation. In addition, theyhave problems regarding safety, namely, they cause a depression ofmyocardial contractility and have a tendency to induce arrhythmias dueto an inhibition of impulse conduction. Beta-adrenoceptor blockers andcalcium antagonists which belong to Class II and IV, respectively, havea defect in that their effects are either limited to a certain type ofarrhythmia or are contraindicated because of their cardiac depressantproperties in certain patients with cardiovascular disease. Theirsafety, however, is higher than that of the antiarrhythmic agents ofClass I.

[0021] The present invention is related to compounds which are useful asinhibitors of potassium channel function. The compounds of the inventionare especially active as inhibitors of voltage-gated potassium channels.The potassium channel inhibitors of the invention may therefore beutilized for the treatment of diseases in which prolongation of cellularaction potentials would be beneficial, which include, but are notlimited to, cardiac arrhythmias. In addition, compounds of the inventionmay be utilized for treating disorders in which induction of cellmembrane depolarization would be beneficial, which include, but are notlimited to, cell proliferative disorders.

[0022] WO 98/04521 (see U.S. Pat. No. 6,083,986) describes a class ofindane potassium channel inhibitors said to be useful for treatingcardiac arrhythmias and cell proliferative disorders.

[0023] It is an object of the present invention to provide compoundswhich are useful for the treatment of diseases in mammals, includinghumans, and especially for the management of diseases which can betreated by inhibiting cell membrane potassium channels, such as thepotassium channels responsible for cardiac I_(Kur) potassium current, orthe potassium channels responsible for T-lymphocyte I_(Kn) potassiumcurrent, and potassium channels containing one of Kv1.5 or Kv1.3α-subunit gene products.

[0024] Another object of the invention is to provide a method oftreating diseases in mammals, including humans, which respond to theinhibition of potassium channel function, which method comprisesadministering to a mammal in need thereof a compound of the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0025] This invention describes compounds and their utility asinhibitors of voltage-dependent potassium channel function, particularlypotassium channels (i.e., I_(Kur), Kv1.5) that could serve as targetsfor the treatment of cardiac arrhythmias especially those occurring inthe atria (e.g., atrial flutter and atrial fibrillation) (Wang et al.,Circ. Res. 73:1061, 1993; Fedida et al., Circ. Res. 73:210, 1993; Wanget al., J. Pharmacol. Exp. Ther. 272:184, 1995), as well as thepotassium channels (i.e., I_(Kn), Kv1.3) that could serve as targets forthe treatment of immunologic diseases (Kaczorowski and Koo, Perspectivesin Drug Discovery and Design 2:233, 1994). Consequently, the presentinvention also provides a method for treating diseases which respond tothe inhibition of potassium channel function, such as cardiacarrhythmias and various immunologic diseases, using the compounds of theinvention.

[0026] The invention is particularly based on our discovery that thecompounds of the following formula (I) are inhibitors of potassiumchannel function. In particular, these compounds have demonstratedactivity against the human potassium channels/currents I_(Kur), I_(Kn),Kv1.5, Kv1.3. As a result, these compounds are useful in the treatmentof cardiac arrhythmias and cell proliferative disorders.

[0027] Thus, in a first aspect, the present invention concerns compoundshaving potassium channel inhibitory activity of the formula (I), or apharmaceutically acceptable salt or prodrug thereof

[0028] wherein,

[0029] A, B, and D are selected from a substituted carbon atom, anitrogen atom or N→O, wherein at least one of A, B, and D is asubstituted carbon atom and at most only one of A, B and D is N→O;

[0030] E and G are each hydrogen or E and G taken together form a bond(site of unsaturation);

[0031] R¹ is selected from hydrogen, alkyl, carbocycloalkyl, aryl,heterocyclo, beteroaryl, alkoxy, aryloxy, and substituted amino;

[0032] Y is selected from a bond (i.e., R¹ and X are directly linked),alkyl, carbocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, andheterocyclo;

[0033] X is one of C═O, C═S or SO₂;

[0034] R² and R³ are independently selected from hydrogen (H), alkyl,carbocycloalkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl,heteroaryl, (heteroaryl)alkyl, aminoalkyl; substituted aminoalkyl,carboxyalkyl, alkoxyalkanoyl, aminoalkanoyl, substituted aminoalkanoyl,alkanoylamidoalkyl, alkanoyl(substituted amido)alkyl, aroylamidoalkyl,aroyl(substituted amido)alkyl, heterocyclocarbonylamidoalkyl,heterocyclocarbonyl(substituted amido)alkyl, heteroaroylamidoalkyl, andheteroaroyl(substituted amido)alkyl;

[0035] R⁴ is selected from alkyl, carbocycloalkyl, aryl, (aryl)alkyl,heteroaryl and heterocyclo;

[0036] R⁵ and R⁶ are each independently selected from hydrogen andalkyl;

[0037] R⁷ is independently selected from hydrogen, alkyl, hydroxy,alkoxy, amino, substituted amino, nitro, cyano, halo, carboxy,alkoxycarbonyl, aminocarbonyl, substituted aminocarbonyl and n is 1, 2or 3;

[0038] Z is selected from hydrogen, alkyl, hydroxy, SH, alkoxy, aryloxy,alkylthio, amino, substituted amino, alkoxycarbonyl, alkanoylamido,aroylamido, heterocyclocarbonylamido, heteroaroylamido,alkanoyl(alkylsubstituted) amido, aroyl(alkylsubstituted)amido,heteroaroyl(alkylsubstituted)amido, and heterocyclocarbonyl(alkylsubstituted)amido;

[0039] with the provisos that

[0040] i) when R⁴ is aryl, then R⁴ is not a 3,4-dialkoxy phenyl, or a3-cycloalkylalkoxy, 4-alkoxy phenyl and

[0041] ii) when A, B, and D are all CH, and Z is H, OR^(a), orNR^(b)R^(c), wherein R^(a) is one of H, (CH₂)_(m)—R⁸ orC(O)—(CH₂)_(m)—R⁸, m is 1 to 5, R⁸ is N(R⁹)₂, N(R⁹)₃L or CO₂R⁹, each R⁹being independently selected from one of H or alkyl, and L is a counterion, R^(b) is H or alkyl; R^(c) is H, alkyl, or CO₂R¹⁰, and R¹⁰ isalkyl; then when R² is hydrogen, or methyl, R³ is not hydrogen, or alkyl(especially methyl), and when R³ is H, or alkyl (especially methyl) thenR² is not H, or methyl.

[0042] In a preferred class of compounds of formula (I), A, B and D aresubstituted carbon atoms, E, G, R⁵, R⁶ and R⁷ are each a hydrogen, Z isselected from hydrogen, alkyl, hydroxyl, amino and substituted amino andthe remaining substituents and provisos are as defined above inconnection with formula (I), as is represented in the following formula(II), (and again including the pharmaceutically acceptable salts orprodrugs thereof)

[0043] In a more preferred subset of compounds of formula (II) (andtheir pharmaceutically acceptable salts, or prodrugs), R¹ is selectedfrom H alkyl, carbocycloalkyl, aryl, and heteroaryl; X is C═O; Y isselected from a bond (i.e., R¹ and X are directly linked), alkyl,carbocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclo; R²and R³ are independently selected from H, alkyl, carbocycloalkyl, aryl,(aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl and(heteroaryl)alkyl;

[0044] R⁴ is selected from aryl and heteroaryl; Z is selected from H,OH, amino and substituted amino.

[0045] In another aspect, the present invention concerns indanecompounds having potassium channel inhibition activity of the formula(III)), or pharmaceutically acceptable salts or prodrugs thereof:

[0046] wherein all of the variables have the meaning ascribed to them inconnection with formula (I) and formula (III) is subject to the sameprovisos as formula (I).

[0047] Yet another preferred subclass of compounds (including theirpharmaceutically acceptable salts or prodrugs) falling within thecompounds of formula (I) is represent by the following formula (IV):

[0048] wherein

[0049] A, B, and D are all CH, or one of A, B, and D is a nitrogen atomor N□O;

[0050] R¹ is selected from hydrogen, alkyl, carbocycloalkyl, aryl,heterocyclo, heteroaryl, alkoxy, aryloxy and substituted amino;

[0051] Y is selected from a bond, alkyl, carbocycloalkyl, alkenyl,alkynyl, aryl, heteroaryl and heterocyclo;

[0052] R² and R³ are independently selected from hydrogen, alkyl,carbocycloalkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl,heteroaryl, (heteroaryl)alkyl, aminoalkyl; substituted aminoalkyl,carboxyalkyl, alkoxyalkanoyl and aminoalkanoyl;

[0053] R⁴ is selected from aryl, heteroaryl and heterocyclo;

[0054] Z is selected from hydrogen, alkyl, hydroxy, SH, alkoxy, aryloxy,alkylthio, amino, substituted amino, alkoxyalkanoyl, alkanoylamido,aroylamido, heteroaroylamido, heterocyclocarbonylamido,alkanoyl(alkylsubstituted)amido, aroyl(alkylsubstituted)amido,heteroaroyl(alkylsubstituted)amido andheterocyclocarbonyl(alkylsubstituted)amido;

[0055] with the provisos that

[0056] i) when R⁴ is aryl, then R⁴ is not a 3,4-dialkoxy phenyl, or a3-cycloalkylalkoxy, 4-alkoxy phenyl and

[0057] ii) when A, B, and D are all CH, and Z is H, OR^(a), orNR^(b)R^(c), wherein R^(a) is one of H, (CH₂)_(m)—R⁸ orC(O)—(CH₂)_(m)—R⁸, m is 1 to 5, R⁸ is N(R⁹)₂, N(R)₃L or CO₂R⁹, each R⁹being independently selected from one of H or alkyl, and L is a counterion, R^(b) is H or alkyl; R^(c) is H, alkyl, or CO₂R¹⁰, and R¹⁰ isalkyl; then when R² is hydrogen, or methyl, R³ is not hydrogen, or alkyl(especially methyl), and when R³ is H, or alkyl (especially methyl) thenR² is not H, or methyl.

[0058] Preferably, R⁴ in the prior embodiments is phenyl per se or aphenyl substituted with one or more groups in the 2 (ortho), 3 (meta),or 4 (para) positions, wherein said groups are selected from C₁₋₅ alkyl,C₁₋₅ alkoxy, cyano, halo and trifluoromethyl. Alternatively, R⁴ is anoptionally substituted heteroaryl, an optionally substituted heterocycloor an optionally substituted carbocycloalkyl, wherein said optionallysubstituted moieties may be substituted with C₁₋₅ alkyl, C₁₋₅ alkoxy,cyano, halo and trifluoromethyl.

[0059] In a preferred class of the compounds of formula (IV) (subject tothe same provisos and including pharmaceutically acceptable salts orprodrugs thereof), A, B and D are all —CH—; Z is selected from hydrogenand hydroxyl, Y is selected from a single bond, alkyl, aryl, heteroaryland heterocyclo, R² is selected from aryl, aralkyl, heteroaryl andheteroaralkyl, and R³ is selected from hydrogen, alkyl, aryl, aralkyl,heteroaryl and heteroaralkyl, and the remaining substituents are asdefined above, as is represented in the following formula (V):

[0060] In other aspects, the present invention concerns compounds havingpotassium channel inhibitory activity of the formula (VI), or apharmaceutically acceptable salt or prodrug thereof

[0061] wherein,

[0062] A, B, and D are selected from a substituted carbon atom, anitrogen atom or N→O, wherein at least one of A, B, and D is asubstituted carbon atom and at most only one of A, B and D is N→O;

[0063] E and G are each hydrogen or E and G taken together form a bond(site of unsaturation);

[0064] R¹ is selected from hydrogen, alkyl, carbocycloalkyl, aryl,heterocyclo, heteroaryl, alkoxy, aryloxy, and substituted amino;

[0065] Y is selected from a bond (i.e., R¹ and X are directly linked),alkyl, carbocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, andheterocyclo;

[0066] X is one of C═O, C═S or SO₂;

[0067] R² is selected from carbocycloalkyl, aryl, (aryl)alkyl,heterocyclo, (heterocyclo)alkyl, heteroaryl, (heteroaryl)alkyl,aminoalkyl; substituted aminoalkyl, carboxyalkyl, alkoxyalkanoyl,aminoalkanoyl, substituted aminoalkanoyl, alkanoylamidoalkyl,alkanoyl(substituted amido)alkyl, aroylamidoalkyl, aroyl(substitutedamido)alkyl, heterocyclocarbonylamidoalkyl,heterocyclocarbonyl(substituted amido)alkyl, heteroaroylamidoalkyl, andheteroaroyl(substituted amido)alkyl;

[0068] R³ is selected from hydrogen (H), alkyl, carbocycloalkyl, aryl,(aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl,(heteroaryl)alkyl, aminoalkyl; substituted aminoalkyl, carboxyalkyl,alkoxyalkanoyl, aminoalkanoyl, substituted aminoalkanoyl,alkanoylamidoalkyl, alkanoyl(substituted amido)alkyl, aroylamidoalkyl,aroyl(substituted amido)alkyl, heterocyclocarbonylamidoalkyl,heterocyclocarbonyl(substituted amido)alkyl, heteroaroylamidoalkyl, andheteroaroyl(substituted amido)alkyl;

[0069] R⁴ is selected from alkyl, carbocycloalkyl, aryl, (aryl)alkyl,heteroaryl and heterocyclo;

[0070] R⁵ and R⁶ are each independently selected from hydrogen andalkyl;

[0071] R⁷ is independently selected from hydrogen, alkyl, hydroxy,alkoxy, amino, substituted amino, nitro, cyano, halo, carboxy,alkoxycarbonyl, aminocarbonyl, substituted aminocarbonyl and n is 1, 2or 3;

[0072] Z is selected from hydrogen, alkyl, hydroxy, SH, alkoxy, aryloxy,alkylthio, amino, substituted amino, alkoxycarbonyl, alkanoylamido,aroylamido, heterocyclocarbonylamido, heteroaroylamido,alkanoyl(alkylsubstituted) amido, aroyl(alkylsubstituted)amido,heteroaroyl(alkylsubstituted)amido, and heterocyclocarbonyl(alkylsubstituted)amido;

[0073] In a preferred class of compounds of formula (VI), A, B and D aresubstituted carbon atoms, E, G, R⁵, R⁶ and R⁷ are each a hydrogen, Z isselected from hydrogen, alkyl, hydroxyl, amino and substituted amino andthe remaining substituents are as defined above in connection withformula (VI), as is represented in the following formula (VII), (andagain including the pharmaceutically acceptable salts or prodrugsthereof)

[0074] In a more preferred subset of compounds of formula (VI) (andtheir pharmaceutically acceptable salts, or prodrugs), R¹ is selectedfrom H alkyl, carbocycloalkyl, aryl, and heteroaryl; X is C═O; Y isselected from a bond (i.e., R′ and X are directly linked), alkyl,carbocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclo; R²is selected from carbocycloalkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyclo)alkyl, heteroaryl and (heteroaryl)alkyl; and R³ is selectedfrom H, alkyl, carbocycloalkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyclo)alkyl, heteroaryl and (heteroaryl)alkyl; R⁴ is selectedfrom aryl and heteroaryl; Z is selected from H, OH, amino andsubstituted amino.

[0075] In still another aspect, the present invention concerns indanecompounds having potassium channel inhibition activity of the formula(VIII)), or pharmaceutically acceptable salts or prodrugs thereof:

[0076] wherein all of the variables have the meaning ascribed to them inconnection with formula (VI).

[0077] Yet another preferred subclass of compounds (including theirpharmaceutically acceptable salts or prodrugs) falling within thecompounds of formula (VI) is represent by the following formula (IX):

[0078] wherein

[0079] A, B, and D are all CH, or one of A, B, and D is a nitrogen atomor N→O;

[0080] R¹ is selected from hydrogen, alkyl, carbocycloalkyl, aryl,heterocyclo, heteroaryl, alkoxy, aryloxy and substituted amino;

[0081] Y is selected from a bond, alkyl, carbocycloalkyl, alkenyl,alkynyl, aryl, heteroaryl and heterocyclo;

[0082] R² is selected from carbocycloalkyl, aryl, (aryl)alkyl,heterocyclo, (heterocyclo)alkyl, heteroaryl, (heteroaryl)alkyl,aminoalkyl; substituted aminoalkyl, carboxyalkyl, alkoxyalkanoyl andaminoalkanoyl;

[0083] R³ is selected from hydrogen, alkyl, carbocycloalkyl, aryl,(aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl,(heteroaryl)alkyl, aminoalkyl; substituted aminoalkyl, carboxyalkyl,alkoxyalkanoyl and aminoalkanoyl;

[0084] R⁴ is selected from aryl, heteroaryl and heterocyclo; and

[0085] Z is selected from hydrogen, alkyl, hydroxy, SH, alkoxy, aryloxy,alkylthio, amino, substituted amino, alkoxyalkanoyl, alkanoylamido,aroylamido, heteroaroylamido, heterocyclocarbonylamido,alkanoyl(alkylsubstituted)amido, aroyl(alkylsubstituted)amido,heteroaroyl(alkylsubstituted)amido andheterocyclocarbonyl(alkylsubstituted)amido.

[0086] Preferably, R⁴ in the prior embodiments is phenyl per se or aphenyl substituted with one or more groups in the 2 (ortho), 3 (meta),or 4 (para) positions, wherein said groups are selected from C₁₋₅ alkyl,C₁₋₅ alkoxy, cyano, halo and trifluoromethyl. Alternatively, R⁴ is anoptionally substituted heteroaryl, an optionally substituted heterocycloor an optionally substituted carbocycloalkyl, wherein said optionallysubstituted moieties may be substituted with C₁₋₅ alkyl, C₁₋₅ alkoxy,cyano, halo and trifluoromethyl.

[0087] In a preferred class of the compounds of formula (IX) (includingpharmaceutically acceptable salts or prodrugs thereof), A, B and D areall —CH—; Z is selected from hydrogen and hydroxyl, Y is selected from asingle bond, alkyl, aryl, heteroaryl and heterocyclo, R² is selectedfrom aryl, aralkyl, heteroaryl and heteroaralkyl, and R³ is selectedfrom hydrogen, alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl, andthe remaining substituents are as defined above, as is represented inthe following formula (X):

[0088] Compounds, (including pharmaceutically acceptable salts orprodrugs thereof), of the prior formulae VI through X, subject to theprovisos attributed to formulae I through V also are contemplated asadditional aspects of the present invention.

[0089] Specific examples of molecules embraced under formulae (I)through (X) are illustrated below.

[0090] As used herein, when a particular radical generally understood tohave a single point of attachment to a core structure, such as an alkylgroup, is identified in connection with a structure that must have twopoints of attachment in the structural core (such as with the element Yin formula (I)), it is understood that the named radical, e.g., alkyl,refers to the parent radical with a hydrogen or a site of unsaturationremoved to create the second point of attachment so as to provide therequired structure.

[0091] The term “alkyl,” as used alone or in combination herein, refersto an unsubstituted or optionally substituted, straight, or branchedchain saturated hydrocarbon group containing from one to eight carbonatoms, preferably from one to five carbons, such as methyl, ethyl,n-propyl, n-butyl, pentyl, hexyl, heptyl, octyl, the various branchchain isomers thereof, such as isopropyl, isobutyl, sec-butyl,tert-butyl, isohexyl and the like. The alkyl group may be optionallysubstituted by one or more substituents, and generally no more thanthree, and most often just one substituent. Preferred optionalsubstituents include halo, alkoxy, amino, mono- and di-substitutedamino, aryl, carboxylic acid, heterocyclo, heteroaryl, carbocycloalkyl,hydroxy, trifluoromethoxy and the like. The term “lower alkyl” refers tosuch alkyl groups containing from one to five carbon atoms.

[0092] The term “alkoxy,” as used alone or in combination herein, refersto an alkyl group, as defined above, covalently bonded to the parentmolecule through an —O— linkage, such as methoxy, ethoxy, propoxy,isopropoxy, butoxy, t-butoxy and the like.

[0093] The term “alkoxyalkyl” refers specifically to an alkyl groupsubstituted with an alkoxy group.

[0094] The term “aryloxy,” as used alone or in combination herein,refers to an aryl group, as defined below, covalently bonded to theparent molecule through an —O— linkage. An example of an aryloxy isphenoxy.

[0095] The term “cycloalkoxy,” as used alone or in combination herein,refers to a carbocycloalkyl group, preferably a cycloalkyl group, asboth defined below, covalently bonded to the parent molecule through an—O— linkage.

[0096] The term “alkylthio,” as used alone or in combination herein,refers to an alkyl group, as defined above, covalently bonded to theparent molecule through an —S— linkage.

[0097] The term “alkenyl,” as used alone or in combination herein,refers to an alkyl group, as defined above, containing one or morecarbon-to-carbon double bonds, preferably one or two double bonds.Examples of alkenyl include ethenylene, propenylene, 1,3-butadienyl, and1,3,5-hexatrienyl.

[0098] The term “alkynyl,” as used alone or in combination herein,refers to an alkyl group, as defined above, containing one or morecarbon-to-carbon triple bonds, preferably one or two triple bonds.

[0099] The term “cycloalkyl,” as used alone or in combination herein,refers to an unsubstituted or optionally substituted, saturated cyclichydrocarbon group containing three to eight carbon atoms. The cycloalkylgroup may optionally be substituted by one or more substituents, andgenerally no more than three, and most often just one substituent.Preferred optional substituents include alkyl, halo, amino, mono- anddi-substituted amino, aryl, hydroxy and the like.

[0100] The term “haloalkyl” is a species of alkyl as defined herein, andparticularly refers to an alkyl, preferably a lower alkyl, substitutedwith one or more halogen atoms, and preferably is a C₁ to C₄ alkylsubstituted with one to three halogen atoms. One example of a haloalkylis trifluoromethyl.

[0101] The term “alkanoyl” as used alone or in combination herein refersto an acyl radical derived from an alkanecarboxylic acid (alkyl-C(O)—),particularly a lower alkanecarboxylic acid, and includes such examplesas acetyl, propionyl, butyryl, valeryl, and 4-methylvaleryl.

[0102] The term “aroyl” means an acyl radical derived from an aromaticcarboxylic acid, such as optionally substituted benzoic or naphthoicacids and specifically including benzoyl and 1-naphthoyl.

[0103] The term “aminocarbonyl” means an amino-substituted carbonyl(carbamoyl or carboxamide) wherein the amino group is a primary amino(—NH₂). Substituted aminocarbonyl refers to secondary (mono-substitutedamino) or tertiary amino (di-substituted amino) group, as defined below,preferably having as a substituent(s) a lower alkyl.

[0104] The term “aminoalkanoyl” means an amino-substituted alkanoylwherein the amino group is a primary amino (-alkyl-C(O)—NH₂). The term“substituted aminoalkanoyl” refers to related secondary(mono-substituted amino) or tertiary amino (di-substituted amino) group,as defined below.

[0105] The term “carbocycloalkyl” when used alone or in combinationrefers to an unsubstituted or optionally substituted, stable, saturatedor partially unsaturated monocyclic, bridged monocyclic, bicyclic, andspiro ring carbocycles of 3 to 15 carbon atoms such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclohexyl,bicyclooctyl, bicyclononyl, spirononyl and spirodecyl. Cycloalkyls arethus one specific subset of carbocycloalkyls, and in the context of thepresent invention constitute a highly preferred subset. The term“optionally substituted” as it refers to “carbocycloalkyl” hereinindicates that the carbocycloalkyl group may be substituted at one ormore substitutable ring positions by one or more groups independentlyselected from alkyl (preferably lower alkyl), alkoxy (preferably loweralkoxy), nitro, monoalkylamino (preferably a lower alkylamino),dialkylamino (preferably a di[lower]alkylamino), cyano, halo, haloalkyl(preferably trifluoromethyl), alkanoyl, aminocarbonyl,monoalkylaminocarbonyl, dialkylaminocarbonyl, alkyl amido (preferablylower alkyl amido), alkoxyalkyl (preferably a lower alkoxy[lower]alkyl),alkoxycarbonyl (preferably a lower alkoxycarbonyl), alkylcarbonyloxy(preferably a lower alkylcarbonyloxy) and aryl (preferably phenyl), saidaryl being optionally substituted by halo, lower alkyl and lower alkoxygroups. Generally, there is no more than one optional substituent.

[0106] The term “heterocyclo” as used, alone or in combination, hereinrefers to an unsubstituted or optionally substituted, stable, saturated,or partially unsaturated, monocyclic, bridged monocyclic, bicyclic, andspiro ring system containing carbon atoms and other atoms selected fromnitrogen, sulfur and/or oxygen. Preferably, a heterocyclo is a 5 or6-membered monocyclic ring or an 8-11 membered bicyclic ring whichconsists of carbon atoms and contains one, two, or three heteroatomsselected from nitrogen, oxygen and/or sulfur. Heterocyclo includesbenz-fused monocyclic carbocycloalkyl groups having at least one suchheteroatom. The term “optionally substituted” as it refers to“heterocyclo” herein indicates that the heterocyclo group may besubstituted at one or more substitutable ring positions by one or moregroups independently selected from alkyl (preferably lower alkyl andincluding haloalkyl (preferably trifluoromethyl)), alkoxy (preferablylower alkoxy), nitro, monoalkylamino (preferably a lower alkylamino),dialkylamino (preferably a di[lower]alkylamino), cyano, halo, alkanoyl,aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkyl amido(preferably lower alkyl amido), alkoxyalkyl (preferably a loweralkoxy[lower]alkyl), alkoxycarbonyl (preferably a lower alkoxycarbonyl),alkylcarbonyloxy (preferably a lower alkylcarbonyloxy) and aryl(preferably phenyl), said aryl being optionally substituted by halo,lower alkyl and lower alkoxy groups. Generally, there is no more thanone optional substituent. Several non-limiting examples of suchheterocyclo groups are illustrated below:

[0107] The heterocyclo group may be, and generally is attached to theparent structure through a carbon atom, or alternatively may be attachedthrough any heteroatom of the heterocyclo that results in a stablestructure.

[0108] The term “heteroaryl” as used alone or in combination, hereinrefers to an unsubstituted or optionally substituted, stable, aromaticmonocyclic or bicyclic ring system containing carbon atoms and otheratoms selected from nitrogen, sulfur and/or oxygen. Preferably, aheteroaryl is a 5 or 6-membered monocyclic ring (optionally benzofused)or an 8-11 membered bicyclic ring which consists of carbon atoms andcontains one, two, or three heteroatoms selected from nitrogen, oxygenand/or sulfur. The term “optionally substituted” as it refers to“heteroaryl” herein indicates that the heteroaryl group may besubstituted at one or more substitutable ring positions by one or moregroups independently selected from alkyl (preferably lower alkyl andincluding haloalkyl (preferably trifluoromethyl)), alkoxy (preferablylower alkoxy), nitro, monoalkylamino (preferably a lower alkylamino),dialkylamino (preferably a di[lower]alkylamino, cyano, halo, alkanoyl,aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkyl amido(preferably lower alkyl amido), alkoxyalkyl (preferably a loweralkoxy[lower]alkyl), alkoxycarbonyl (preferably a lower alkoxycarbonyl),alkylcarbonyloxy (preferably a lower alkylcarbonyloxy) and aryl(preferably phenyl), said aryl being optionally substituted by halo,lower alkyl and lower alkoxy groups. Generally, there is no more thanone optional substituent. Several non-limiting examples of suchheteroaryl groups are illustrated below:

[0109] The heteroaryl group may be, and generally is attached to theparent structure through a carbon atom or alternatively may be attachedthrough any heteroatom of the heteroaryl that results in a stablestructure. In the foregoing structures it also is contemplated that anitrogen could be replaced with an N-oxide.

[0110] Both heterocyclo and heteroaryl also are intended to embracebenzo fused structures such as 1,2-methylenedioxybenzene and1,4-benzodioxan.

[0111] The specific chemical nature of the optionally substitutedheterocyclo and heteroaryl groups for the terminal moieties R¹and R² inthe prior identified potassium channel inhibitor compounds is notnarrowly critical and, as noted above, a wide variety of substituentgroups are contemplated. Preferably, the substituents for theheterocyclo and heteroaryl groups are selected such that the totalnumber of carbon and hetero atoms comprising the substitutedheterocyclos and heteroaryls is no more than about 20.

[0112] The terms “halo” and “halogen” as used herein to identifysubstituent moieties, represent fluorine, chlorine, bromine or iodine,preferably chlorine or fluorine.

[0113] The term “aryl,” when used alone or in combination, refers to anunsubstituted or optionally substituted monocyclic or bicyclic aromatichydrocarbon ring system having 6 to 12 ring carbon atoms. Preferred areoptionally substituted phenyl, 1-naphthyl, or 2-naphthyl groups. Thearyl group may optionally be substituted at one or more substitutablering positions (generally at no more than three positions and most oftenat one or two positions) by one or more groups independently selectedfrom alkyl (including haloalkyl (preferably trifluoromethyl anddifluoromethyl)), alkenyl, alkynyl, alkoxy, aryloxy, nitro, hydroxy,amino, mono- and di-substituted amino, cyano, halo, alkanoyl,aminocarbonyl, carboxylic acid, carboxylic acid esters, carboxylic acidamide, an optionally substituted phenyl (optionally substituted by halo,lower alkyl and lower alkoxy groups), heterocyclo, or heteroaryl.Preferably, the aryl group is phenyl optionally substituted with up tofour and more usually with one or two groups, preferably selected fromlower alkyl, lower alkoxy, as well as cyano, trifluoromethyl and halo.

[0114] The terms “aralkyl” and “(aryl)alkyl,” alone or in combinationare a species of alkyl as defined herein, and particularly refers to analkyl group as defined above in which one hydrogen atom is replaced byan aryl group as defined above, and includes benzyl, and 2-phenylethyl.

[0115] The terms “(heterocyclo)alkyl” and “(heteroaryl)alkyl” alone orin combination can be considered a species of alkyl as defined herein,and particularly refers to an to an alkyl group as defined above inwhich one hydrogen atom is replaced by a heterocyclo group as definedabove, or by a heteroaryl group as defined above.

[0116] The term “alkoxycarbonyl” alone or in combination means a radicalof the formula —C(O)-alkoxy, in which alkoxy is as defined above.

[0117] The term “alkylcarbonyloxy” alone or in combination means aradical of the formula —O—C(O)-alkyl, in which alkyl is as definedabove.

[0118] The term “alkoxyalkanoyl” alone or in combination means a radicalof the formula -alkyl-C(O)—O-alkyl.

[0119] The term “carboxyalkyl” alone or in combination means a radicalof the formula -alkyl-C(O)—OH.

[0120] As used in connection with formula (I) and elsewhere in thisapplication, the term “substituted carbon atom” means a ring carbonsubstituted with one of the group R⁷, or the radical —N(R²)(XYR¹).

[0121] The term “substituted amino” embraces both “mono anddi-substituted amino.” These terms, alone, or in combination, mean aradical of the formula —NR′R″, where, in the case of mono-substitution,one of R′ and R″ is a hydrogen and the other is selected from alkyl,carbocycloalkyl, aryl, heterocyclo, (aryl)alkyl, (heterocyclo)alkyl,heteroaryl and hetero(aryl)alkyl; in the case of di-substitution, R′ andR″ are independently selected from alkyl, carbocycloalkyl, aryl,heterocyclo, and heteroaryl, or R′ and R″ together with the nitrogenatom to which they are both attached form a three to eight-memberedheterocyclo or heteroaryl radical.

[0122] The term “amido” refers to the group (—NH—) and the term“substituted amido” embraces a radical of the formula (—NR′—) where R′has the meaning above in connection with substituted amino.

[0123] The terms “alkanoylamido,” “aroylamido,”“heterocyclocarbonylamido” and “heteroaroylamido” mean groups of theformula R—C(O)—NH— where R is an alkyl, aryl, heteroaryl or heterocyclo.

[0124] The terms “heteroaroyl” and “heterocyclocarbonyl” when used aloneor in combination means groups of the formula R—C(O)— where R is aheteroaryl or heterocyclo.

[0125] Unless otherwise defined, the term “optionally substituted” asused herein, refers to the substitution of a ring system at one or morepositions with one or more groups selected from: C₁₋₅ alkyl, C₁₋₅alkoxy, an optionally substituted phenyl, cyano, halo, trifluoromethyl,C₁₋₅ alkoxycarbonyl, C₁₋₅ alkyl carbonyloxy, mono- and bis-(C₁₋₅alkyl)-carboxamide, C₁₋₅ alkyl amido, nitro, and mono- and bis-(C₁₋₅alkyl)-amino.

[0126] Applicants recognize that there may be some overlap in some ofthe definitions of the various radical groups. Specific groups arementioned, however, such as (aryl)alkyl, and may be particularlyidentified in the claims, in order to emphasize their positive inclusionin the described subject matter, as not only an optional substituent.

[0127] The term “treating” as used herein, describes the management andcare of a patient afflicted with a condition, disease or disorder forwhich the administration of a compound of the present invention altersthe action or activity of a potassium channel to prevent the onset ofsymptoms or complications associated with the condition, disease ordisorder, to alleviate the symptoms or complications caused by thecondition, disease or disorder, or to eliminate the condition, diseaseor disorder altogether.

[0128] Certain indane compounds of the previous formulae useful aspotassium channel inhibitors in accordance with the present inventioncan be prepared in accordance with the following Scheme 1:

[0129] Compounds of the invention of formula II where Z is hydrogen maybe prepared starting with a nitro indanone (A), which in step (1) isreductively aminated in the presence of ammonium acetate (employing amolar ratio of nitro indanone:ammonium acetate within the range fromabout 1:1 to about 1:30) and a reducing agent such as sodiumcyanoborohydride in an inert organic solvent such as methanol to formthe nitro-amino compound (B). The nitro-amino compound (B) then isreacted with a sulfonylating agent (employing a molar ratio of Step (1)product to sulfonylating agent within the range from about 1:1 to about10:1) in the presence of a base such as triethylamine or pyridine and inan inert organic solvent such as tetrahydrofuran or dichloromethane toform the sulfonylated compound (C).

[0130] The sulfonylated compound (C) is then subjected tonitro-reduction by treatment with a suitable reducing agent such assodium borohydride in the presence of nickel chloride in an organicsolvent such as tetrahydrofuran and/or methanol to form the aniline (D).Aniline (D) is then derivatized by treatment with an alkylating agentsuch as an alkyl halide (R²X where X is Cl, Br, or I) in the presence ofa base such as potassium carbonate in an inert solvent such asacetonitrile to form the secondary amine (E). Alternatively, aniline (D)can be derivatized by reductive alkylation using an aldehyde and adrying agent such as sodium sulfate followed by treatment with areducing agent such as sodium borohydride in an organic solvent such asmethanol or ethanol.

[0131] The secondary amine (E) thereafter undergoes an acylation in step(5) by reacting the secondary amine (E) with an acylating agent such asan acid chloride (which may be prepared in situ from the correspondingcarboxylic acid by methods known in the literature) in the presence of abase such as triethylamine or pyridine in an inert organic solvent suchas tetrahydrofuran or dichloromethane to form the amide compounds (F) offormula II where X is C═O. The secondary amine (E) can also be reactedwith a sulfonylating agent under conditions described above to formsulfonamide compounds of formula II (compound (F)) where X is SO₂. Thesecondary amine (E) can also be reacted with an isocyanate in an organicsolvent such as tetrahydrofuran or dichloromethane to form ureacompounds of formula II where X is C═O, Y is a bond, and R¹ is asubstituted amino.

[0132] The starting nitro indanone, compound (A), the amino compound(B), the sulfonamide (C), and the aniline (D) in General Scheme 1 may beprepared as described in N. Castle et al., WO 9804521, see also U.S.Pat. No. 6,083,986 incorporated herein by reference.

[0133] A synthetic approach to prepare compounds of formula II where Zis hydroxyl is provided by the following Scheme 2 (Steps 1-8). In step(1), reduction of a nitro indanone (using NaBH₄ for example) gives thecorresponding alcohol;

[0134] In the next step (2), the product of step (1) is subjected to anacid catalyzed dehydration (pTSA/Toluene) to give the correspondingindene.

[0135] Then in step (3) the double bond of the indene product of step(2) is oxidized (e.g. using M-CPBA/CH₂Cl₂) to give the correspondingepoxide

[0136] In step (4), the epoxide of step (3) is aminated (for instanceusing ammonium hydroxide) to give the corresponding amino alcohol.

[0137] The amino-alcohol of step (4) is sulfonylated, for example usinga sulfonyl chloride, to attach an R⁴—SO₂— moiety. The amino-alcohol isreacted in a suitable solvent with the sulfonyl chloride (or a sulfonylanhydride) in the presence of an acid scavenger. Suitable solvents inwhich the reaction can be conducted include methylene chloride andtetrahydrofuran. Suitable acid scavengers include triethylamine andpyridine.

[0138] In step (6), the nitro moiety of the sulfonylated product of step(5) is reduced (SnCl₂) to give the corresponding aniline.

[0139] The aniline formed in step (6) can then be derivatized (step (7))by treatment with an alkylating agent such as an alkyl halide (R²X whereX is Cl, Br, or I) in the presence of a base such as potassium carbonatein an inert solvent such as acetonitrile to form a secondary amine.Alternatively, the aniline formed in step (6) can be derivatized byreductive alkylation using an aldehyde and a drying agent such as sodiumsulfate followed by treatment with a reducing agent such as sodiumborohydride in an organic solvent such as methanol or ethanol.

[0140] As in Scheme 1, the so-formed secondary amine thereafterundergoes an acylation in step (8) with an acylating agent such as anacid chloride (which may be prepared in situ from the correspondingcarboxylic acid by methods known in the literature) in the presence of abase such as triethylamine or pyridine in an inert organic solvent suchas tetrahydrofuran or dichloromethane to form the desired amide where Xis C═O. The resulting amide (X is C═O) can be readily converted to thecorresponding thioamide (X is C═S) via known literature procedures(e.g., through the use of Lawesson's reagent. The secondary amine couldalso be reacted with a sulfonylating agent under conditions describedabove to form the related sulfonamide compounds where X is SO₂.Additionally, the secondary amine could also be reacted with anisocyanate in an organic solvent such as tetrahydrofuran ordichloromethane to form a urea where X is C═O, Y is a bond, and R¹ is asubstituted amino.

[0141] Those skilled in the art will appreciate additional techniquesand raw materials suitable for preparing other compounds falling withinthe scope of the present invention, as for example are illustrated inthe subsequent specific examples. For instance, the skilled worker willreadily appreciate the advantage of employing protecting groups, andwill readily understand their application in a specific syntheticapproach to improve the yield of desired products. For example, oneskilled in the art will recognize that there are a variety of protectinggroups as discussed in “Protective Groups in Organic Synthesis”, T. W.Green and P. G. M. Wuts (1999).

[0142] It is recognized that there is generally at least one and oftenmore than one chiral center in the compounds falling within the scope ofthe present invention and thus such compounds will exist as variousstereoisomeric forms. Applicants intend to include all the variousstereoisomers within the scope of the invention. Thus, this invention isintended to include the cis and trans isomers and the correspondingenantiomers of the compounds of formula I-V. Though the compounds may beprepared as racemates and can conveniently be used as such, individualenantiomers also can be isolated or preferentially synthesized by knowntechniques if desired. Such racemates and individual enantiomers andmixtures thereof are intended to be included within the scope of thepresent invention.

[0143] The present invention also encompasses the pharmaceuticallyacceptable prodrugs of the compounds of Formula I. A prodrug is a drugwhich has been chemically modified and may be biologically inactive atits site of action, but which is degraded or modified by one or moreenzymatic or other in vivo processes to the parent bioactive form.Generally, a prodrug has a different pharmacokinetic profile than theparent drug such that, for example, it is more easily absorbed acrossthe mucosal epithelium, it has better salt formation or solubilityand/or it has better systemic stability (e.g., an increased plasmahalf-life).

[0144] Those skilled in the art recognize that chemical modifications ofa parent drug to yield a prodrug include: (1) terminal ester or amidederivatives which are susceptible to being cleaved by esterases orlipases; (2) terminal peptides which may be recognized by specific ornonspecific proteases; or (3) a derivative that causes the prodrug toaccumulate at a site of action through membrane selection, andcombinations of the above techniques. Conventional procedures for theselection and preparation of prodrug derivatives are described in H.Bundgaard, Design of Prodrugs, (1985). Those skilled in the art arewell-versed in the preparation of prodrugs and are well-aware of itsmeaning.

[0145] The compounds of the present invention can be used in their neatform or in the form of pharmaceutically-acceptable salts derived frominorganic or organic acids, or in the form of their esters, amides,complexes, chelates, hydrates, stereoisomers, crystalline or amorphousforms, metabolites, metabolic precursors, or prodrugs. In the practiceof the present invention, compounds of the present invention in theirneat form will generally have a molecular weight of 800 or below,usually 600 or below.

[0146] Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts of compounds of the present inventioninclude such inorganic acids as hydrochloric acid, sulphuric acid andphosphoric acid and such organic acids as maleic acid, succinic acid andcitric acid. These salts thus include, but are not limited to, thefollowing: acetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate,glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate,nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate,persulfate, 3-phenylpropionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate.

[0147] Also, the basic nitrogen-containing groups can be quaternizedwith such agents as lower alkyl halides, such as methyl, ethyl, propyl,and butyl chlorides, bromides and iodides; dialkyl sulfates, likedimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides suchas decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides,aralkyl halides like benzyl and phenethyl bromides and others. Water oroil soluble or dispersible products are thereby generally obtained.

[0148] The pharmaceutically acceptable salts of the compounds of thepresent invention also can exist as various solvates, such as withwater, methanol, ethanol, dimethylformamide, ethyl acetate and the like.Mixtures of such solvates also can be prepared. Such solvates are withinthe scope of the present invention.

[0149] The pharmacological profile of the potassium channel inhibitoryactivity of the compounds of the present invention can be readilyassessed by those skilled in the art using routine experimentation, suchas the procedures and techniques illustrated in the examples whichfollow. Assays for assessing the activity of particular compounds mayemploy cells stably transfected to express a specific potassium channel,as well as native mammalian cells. In particular, stable transfectedcells, transfected to express a specific potassium channel, which havebeen treated with a voltage dependent fluorescent dye, such asbis(1,3-dibutylbarbituric acid)trimethine oxonol, can be used to gaugethe inhibitory activity of potassium channel inhibitor compounds,possibly in comparison to known inhibitors. Alternatively, such cellscan be primed with a detectible species, such as ⁸⁶Rb, and thenchallenged with a particular compound, under conditions otherwisesuitable for activating the potassium channel, to assess the potassiuminhibitory activity of the compound. The potassium channel inhibitoryactivity of a compound also can be determined using isolated mammaliancells and the whole cell configuration of the known patch clamptechnique (Hamill et al., Pflugers Archiv 391:85, 1981). These and otherknown techniques can be readily employed by those skilled in the art toassess the activity level of the potassium channel inhibitor compoundsof the present invention.

[0150] The compounds of the present invention may be administered by avariety of routes including orally, parenterally, sublingually,intranasally, by inhalation spray, rectally, or topically in dosage unitformulations containing conventional nontoxic pharmaceuticallyacceptable carriers, adjuvants, and vehicles as desired. The termparenteral as used herein includes subcutaneous injections, intravenous,intramuscular, intracardiac injection, or infusion techniques. Topicaladministration may also involve the use of transdermal administrationsuch as transdermal patches or iontophoresis devices.

[0151] Injectable preparations, for example, sterile injectable aqueousor oleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,2-propanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

[0152] Suppositories for rectal administration of the drug can beprepared by mixing the drug with a suitable nonirritating excipient suchas cocoa butter and polyethylene glycols which are solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum and release the drug.

[0153] Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose, lactose, or starch. Such dosage forms may also comprise, as isnormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

[0154] Liquid dosage forms for oral administration may includepharmaceutically acceptable emulsions, solutions, suspensions, syrupsand elixirs containing inert diluents commonly used in the art, such aswater. Such compositions may also comprise adjuvants, such as wettingagents, emulsifying and suspending agents, and sweetening, flavoring andperfuming agents.

[0155] The compounds of the present invention can also be administeredin the form of liposomes. As is known in the art, liposomes aregenerally derived from phospholipids or other lipid substances.Liposomes are formed as mono- or multi-lamellar hydrated liquid crystalsthat are dispersed in an aqueous medium. Any non-toxic physiologicallyacceptable and metabolizable lipid capable of forming liposomes can beused. The present compositions in liposome form can contain, in additionto a compound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andphosphatidyl cholines (lecithins), both natural and synthetic. Methodsto form liposomes are known in the art. See, for example, Prescott, Ed.,Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y.(1976), p. 33, et seq.

[0156] To select preferred compounds from less preferred compounds, oneuses by example the in vitro assays detailed under the sub-headingBioAssays hereafter described. Typically, a preferred compound willproduce half maximal blocking activity at a concentration below about 5μM, preferably below about 1 μM, more preferably below about 100 nM andmost preferably below about 10 nM in the in vitro assays described. Oneof ordinary skill will recognize that the final and optimum dose andregimen will be determined empirically for any given drug.

[0157] Total daily dose administered to a host in single or divideddoses may be an amount, for example, from 0.001 to 100 mg of activeingredient per kg body weight on a daily basis and more usually 0.01 to10 mg/kg/day. Dosage unit compositions may contain such amounts ofsubmultiples thereof to make up the daily dose. It is anticipated that atherapeutically effective serum concentration of active ingredient willbe 10 nM to 10 μM (5 ng/ml to 5 μg/ml).

[0158] The amount of active ingredient that may be combined with carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

[0159] It will be understood, however, that the specific dose level forany particular patient will depend upon a variety of factors includingthe activity of the specific compound employed, the age, body weight,general health, sex, and diet of the patient, the time ofadministration, the route of administration, the rate of excretion,whether a drug combination is used, and the severity of the particulardisease.

[0160] Using the processes described hereinabove, the followingcompounds (each assigned a unique number identifier) can be synthesized:

[0161] The present invention is further explained in greater detail inthe Examples which follow. These experimental examples are intended asillustrative of the invention, and are not to be taken as limitingthereof. Unless otherwise indicated, all references to parts andpercentages are based on weight and all temperatures are expressed indegrees Celsius. The scope of the invention is not construed as merelyconsisting of the following examples.

EXAMPLES

[0162] Compound Preparation

[0163] Compounds 97 and 98 and related amino indanes are prepared asdescribed in N. Castle et al WO9804521 (See also U.S. Pat. No. 6,083,986incorporated herein by reference); D. Buckle et al J Med. Chem. 1991,34, 919-926 (and references cited therein) and J. Tedder et al.,EP0321175

[0164] Separation of the enantiomers of compound 97 and compound 98 canbe accomplished by chiral HPLC using a Chiralpak AS column (ChiralTechnologies, Inc.) for compound 97 and a Chiralpak OJ column (ChiralTechnologies, Inc.) for compound 98. Asymmetric synthetic methods canalso be used to separate the enantiomers of compound 97 and compound 98.For example, see N. Castle et al., WO 98/04521 (See also U.S. Pat. No.6,083,986).

[0165] The resolution of racemic trans-2-phenylcyclopropanecarboxylicacid to give the (+)—(S) and (−)—(R) isomers is accomplished asdescribed in Macromolecules, 1971, 4, 718-719.

Example 1

[0166] Preparation of Compound 99

[0167] To a stirred solution of Compound 97 (200 mg, 0.948 mmol) inmethanol (5 mL) at room temperature was added1-methyl-2-imidazolecarboxaldehyde (125 mg, 1.13 mmol) and anhydroussodium sulfate (673 mg, 4.74 mmol). The reaction mixture was heated at50° C. for six hours under nitrogen. The excess sodium sulfate wasfiltered from the reaction mixture while it was still warm and thefiltrate was cooled to room temperature. Sodium borohydride (103 mg,2.72 mmol) was added to the filtrate and it was stirred for 15 hours atroom temperature. The solution was quenched with saturated aqueoussodium bicarbonate solution and the methanol was removed by rotaryevaporation. The resulting mixture was diluted with water and extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate, filtered, and concentrated. The residue was recrystallized froma minimum amount of hot ethyl acetate to give Compound 99 (229 mg, 59%)as a white solid. The mother liquor was concentrated and subjected toflash column chromatography on silica gel using 9:1 ethylacetate:methanol as the eluent to provide additional Compound 99 (39mg). ¹H NMR (300 MHZ, d₆-acetone) δ 7.90 (d, 2H, J=8.2 Hz), 7.47 (d, 2H,J=8.1 Hz), 6.99 (s, 1H), 6.92 (d, 1H, J=8.2 Hz), 6.82 (d, 1H, J=0.8 Hz),6.67 (dd, 1H, J=2.0, 8.1 Hz), 6.50 (s, 1H), 5.14 (s, 1H), 4.70 (m, 2H),4.21 (s, 2H), 3.70 (s, 3H), 2.75, (q 2H, J=7.6 Hz), 2.67 (dd, 1H, J=3.3,8.9 Hz), 2.56 (m, 1H), 2.12 (m, 1H), 1.69 (m, 1H), 1.25 (t, 3H, J=7.6Hz). ”³C NMR (75 MHZ, d₆-acetone) δ 149.4, 147.4, 145.8, 143.4, 139.4,131.5, 128.3, 126.9, 125.6, 124.6, 121.8, 113.5, 108.1, 58.7, 40.4,34.2, 31.9, 28.5, 28.3, 14.3.

[0168] The following compounds in Example 2 and Example 3 weresynthesized using the procedures described in Example I using Compound97 and the appropriate aldehyde.

Example 2

[0169] Preparation of Compound 100

[0170] Compound 100 was obtained by reacting Compound 97 with 3-pyridinecarboxaldehyde under the reaction conditions described in Example 1 in78% yield. Purification was accomplished by flash column chromatographyon silica gel using 6:2:2 ethyl acetate:dichloromethane:hexanes as theeluent. ¹H NMR (300 MHZ, CDCl₃) δ 8.47 (s, 1H), 8.45 (d, J=4.8 Hz, 1H),7.81 (d, J=8.1 Hz, 2H), 7.63 (d, J=7.8 Hz, 1H), 7.31 (d, J=8.1 Hz,2H),7.26-7.20(m, 1H),6.94(d, J=8.1 Hz, 1H), 6.45 (d, J=7.8 Hz, 1H), 6.41(s, 1H), 5.43 (s, J=9.0 Hz, 1H), 4.73 (q, J=7.8 Hz, 1H), 4.19 (s, 2H),2.78-2.54 (m, 4H), 2.30-2.20 (m, 1H), 1.73-1.61 (m, 1H), 1.23 (t, J=7.5Hz, 3H);. ¹³C NMR (75 MHZ, CDCl₃) δ 149.5, 149.0, 148.6, 147.0, 143.6,138.7, 135.4, 134.9, 132.1, 128.6, 127.2, 125.4, 123.6, 113.6, 108.4,58.9, 46.0, 35.0, 29.1, 28.8, 15.2

Example 3

[0171] Preparation of Compound 101

[0172] Compound 101 was obtained by reacting Compound 97 with6-methyl-2-pyridine carboxaldehyde under the reaction conditionsdescribed in Example 1 in 66% yield. Purification was accomplished byrecrystallization from ethyl acetate/hexane. ¹H NMR (300 MHZ, CDCl₃) δ7.81 (d, J=7.8 Hz, 2 M, 7.50 (t, J=7.8 Hz, 1H), 7.31 (d, J=7.8 Hz, 2H),7.06 (d, J=7.02 (d, J=7.8 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.50 (d,J=7.8, 1H), 6.38 (s, 1H), 5.10 (d, J=8.7 Hz, 1H), 4.72 (q, J=7.5 Hz,1H), 4.24 (s, 2H), 2.70 (q, J=7.2 Hz, 2H), 2.63-2.56 (m, 2H), 2.56 (s,3H), 2.25-2.22 (m, 11H), 1.71-1.62 (m, 11H), 1.24 (t, J=7.2 Hz, 3H); ¹³CNMR (75 MHZ, CDCl₃) δ 158.0, 157.5, 149.4, 147.4, 143.3, 138.6, 136.9,131.4, 128.6, 127.3, 125.2, 121.7, 118.7, 113.8, 108.3, 58.9, 49.4,35.0, 29.1, 28.8, 24.5, 15.2

Example 4

[0173] Preparation of Compound 102

[0174] To a stirred solution of Compound 98 (294 mg, 0.88 mmol) inmethanol (10 mL) at room temp was added 3-pyridine carboxaldehyde (0.12mL, 1.27 mmol) followed by anhydrous sodium sulfate (480 mg, 3.38 mmol).The reaction mixture was heated at 55° C. for 24 hours under nitrogen atwhich time TLC analysis indicated that no starting material remained.The reaction was cooled to 0° C. and treated with sodium borohydride (53mg, 1.40 mmol) in one portion. After 15 minutes at 0° C. the coolingbath was removed and the reaction was stirred at room temperature forthree hours. The methanol was removed by rotary evaporation and theresidue was treated with ethyl acetate and water. The organic layer wasseparated, washed with saturated sodium chloride solution, dried overanhydrous sodium sulfate, filtered and concentrated. The residue waspurified by flash column chromatography on silica gel using 8:1:1 ethylacetate:hexane:acetonitrile as the eluent to provide Compound 102 (197mg, 53%) as a white foam. ¹H NMR (300 MHZ, CDCl₃) δ 8.41 (S, 1H), 8.33(d, J=4.2 HZ, 1H), 7.82 (d, J=8.1 Hz, 2H), 7.57 (d, J=7.8 Hz, 1H), 7.25(d, J=8.1 Hz, 2H), 7.16 (dd, J=4.8 and 7.5 Hz, 1H), 6.86 (d, J=8.1 Hz,1H), 6.59 (d, J=7.8 Hz, 1H), 6.41 (d, J=6.9 Hz, 1H), 6.20 (s, 1H), 3.95(t, J=6.9 Hz, 1H, 4.30 (q, J=7.5 Hz, 1H), 4.11 (s, 2H), 3.92 (broad s,1H), 3.01 (dd, J=7.5 and 15.3 Hz, 1H), 2.67-2.60 (m, 3H), 1.19 (t, J=7.5Hz, 3H); ¹³C NMR (75 MHZ, CDCl₃) δ 149.7, 148.7, 148.2, 147.3, 140.2,137.6, 135.5, 135.1, 128.7, 128.3, 127.4, 125.7, 123.7, 113.7, 108.2,80.8, 65.6, 45.8, 37.0, 28.8, 15.2

Example 5

[0175] Preparation of Compound 103

[0176] To a solution of Compound 97 (100 mg, 0.32 mmol) in1-methyl-2-pyrrolidinone (0.7 mL) at room temperature was added2-chloropyrimidine (40 mg, 0.35 mmol). The reaction mixture was heatedat 140° C. for 21 hours. The crude reaction mixture was directlysubjected to flash column chromatography on silica gel eluting withhexane:ethyl acetate (3:2 then 1:1) to give Compound 103 (49 mg, 39%) asa white solid. ¹H NMR (300 MHZ, CDCl₃) δ (ppm): 8.33 (2H, d, J=4.9 Hz),7.87 (2H, d, J=8.3 Hz), 7.40 (1H, dd, J=1.9, 8.0), 7.33 (2H, d, J=8 Hz),7.31 (1H, s), 7.14 (1H, d, J=8.2 Hz), 6.69 (1H, t, J=4.8), 5.18 (1H, d,J=8.9 Hz), 4.83 (1H, q, J=8.4 Hz), 2.91-2.81 (1H, m), 2.74-2.64 (1H, m),2.71 (2H, q, J=7.7 Hz), 2.41-2.31 (1H, m), 1.87-1.72 (2H, m), 1.25 (3H,t, J=7.7 Hz).

Example 6

[0177] Preparation of Compound 10

[0178] To a stirred solution of Compound 99 (65 mg, 0.16 mmol) inanhydrous THF (1.5 mL) at room temperature was added triethylamine(0.027 mL, 0.20 mmol) followed by hydrocinnamoyl chloride (29 mg, 0.17mmol). The reaction mixture was stirred at room temperature for 6 hours.Saturated aqueous sodium bicarbonate solution was added and theresulting mixture was extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate, filtered, and concentrated. Theresidue was purified by flash column chromatography on silica gel using10:1:1 ethyl acetate:dichloromethane:hexanes as the eluent to giveCompound 10 (59 mg, 69%) as a white foam. ¹H NMR (300 MHZ, d6-acetone) δ7.87 (d, 2H, J=8.4 Hz), 7.48 (d, 2H, J=8.2-Hz), 7.26 (m, 4H), 7.15 (d,1H, J=7.2 Hz), 7.08 (d, 2H, J=7.7 Hz), 6.94 (s, 1H), 6.76 (d, 1H, J=7.8Hz), 6.65 (d, 1H, J=7.8 Hz), 4.92 (m, 1H) 4.77 (m, 2H), 3.59 (s, 3H),2.81 (q, 2H, J=6.9 Hz), 2.74 (m, 4H), 2.24 (m, 3H), 1.76 (m, 1H), 1.26(t, 3H, 7.6 Hz). ³C NMR (75 MHZ, d6-acetone) δ 170.8, 149.2, 144.2,143.7, 142.8, 141.5, 140.0, 128.6, 128.4, 128.3, 128.3, 127.2, 126.9,125.9, 125.2, 124.3, 121.6, 58.3, 35.8, 34.4., 32.2, 31.2, 29.8, 28.4,14.8.

[0179] The following compounds in Example 7 to Example 10 weresynthesized using the procedures described in Example 6 using Compound99 and the appropriate acid chloride.

Example 7

[0180] Preparation of Compound 37

[0181] Compound 37 was obtained by reacting Compound 99 with3-chlorobenzoyl chloride in the presence of triethylamine as describedin Example 6 in 67% yield. Purification was accomplished by flash columnchromatography using EtOAc as the eluent. ¹H NMR (300 MHZ, d6-acetone) δ7.87 (d, 2H, J=8.2 Hz), 7.48 (d, 2H, J=8.4 Hz), 7.26 (m, 1H), 7.14 (m,1H), 7.08 (d, 1H, J=8.7 Hz), 7.00 (s, 1H), 6.96 (d, 1H, J=8.0 Hz), 6.86(d, 1H, J=11.1 Hz), 6.79 (s, 1H), 5.11 (d, 1H, J=15.2 Hz), 4.94 (d, 1H,J=15.2 Hz) 4.69 (m, 1H), 3.75 (s, 3H), 2.77 (q, 2H, J=7.7 Hz), 2.72 (m,1H), 2.63 (m, 1H), 2.22 (m, 1H), 1.72 (m, 1H) 1.27 (t, 3H, 7.7 Hz). ¹³CNMR (75 MHZ, d₆-acetone) δ 167.9, 149.2, 144.1, 143.6, 141.9, 141.5,139.9, 138.5, 133.2, 129.4, 129.3, 128.6, 128.4, 128.3, 127.2, 127.1,126.9, 124.8, 123.8, 121.6, 58.3, 45.2, 34.5, 32.3, 14.8.

Example 8

[0182] Preparation of Compound 45

[0183] Compound 45 was obtained by reacting Compound 99 with m-anisoylchloride in the presence of triethylamine as described in Example 6 in90% yield. Purification was accomplished by flash column chromatographyusing 10:1 ethyl acetate:hexanes as the eluent. ¹H NMR (300 MHZ,d₆-acetone) δ 7.89 (d, 2H, J=8.2 Hz), 7.48 (d, 2H, J=8.2 Hz), 7.24 (d,1H, J=8.6 Hz), 7.07 (t, 1H, J=8.0 Hz), 7.01 (s, 1H), 6.91 (d, 1H, J=8.0Hz), 6.79 (m, 5H), 5.16 (d, 1H, J=15.1 Hz), 4.92 (d, 1H, J=15.2 Hz),4.68 (dd, 1H, J=7.8, 15.8 Hz), 3.77 (s, 3H), 3.63 (s, 3H), 2.76 (q, 2H,J=7.7 Hz), 2.71 (dd, 1H, J 3.1, 8.4 Hz), 2.63 (m, 1H), 2.24 (m, 1H),1.73 (m, 1H), 1.26 (t, 3H, J=7.6 Hz).

Example 9

[0184] Preparation of Compound 46

[0185] Compound 46 was obtained by reacting Compound 99 with3-cyclopentylpropionyl chloride in the presence of triethylamine asdescribed in Example 6 in 44% yield. Purification was accomplished byflash column chromatography using 10:1 ethyl acetate:hexanes as theeluent. ¹H NMR (300 MHZ, d₆-acetone) δ 7.89 (d, 2H, J=8.1 Hz), 7.45 (d,2H, J=8.2 Hz), 7.28 (m, 1H), 7.13 (d, 1H, J=8.0 Hz), 6.97 (s, 1H), 6.91(d, 1H, J=8.0 Hz), 6.89 (d, 1H, J=6.7 Hz), 6.68 (d, 1H, J=14.8 Hz), 4.94(d, 1H, J=15.0 Hz), 4.78 (m, 2H), 3.68 (s, 3H), 2.88 (m, 4H), 2.76 (q,2H, J=7.5 Hz), 2.70 (m, 1H), 2.29 (m, 1H), 1.95 (m, 2H), 1.82 (m, 1H),1.50 (m, 8H), 1.26 (t, 3H, J=7.6 Hz).

Example 10

[0186] Preparation of Compound 47

[0187] Compound 47 was obtained by reacting Compound 99 with3,3-dimethylacryloyl chloride in the presence of triethylamine asdescribed in Example 6 in 37% yield. Purification was accomplished byflash column chromatography using 10:1 ethyl acetate:hexanes as theeluent. ¹H NMR (300 MHZ, d6-acetone) δ 7.88 (d, 2H, J=8.3 Hz), 7.44 (d,2H, J=8.4 Hz), 7.26 (d, 1H, J=8.6 Hz), 7.10 (d, 1H, J=7.9 Hz), 6.96 (s,1H), 6.89 (d, 1H, J=8.0 Hz), 6.71 (s, 1H), 5.39 (s, 1H), 4.98 (d, 1H,J=15.1 Hz), 4.78 (m, 2H), 3.71 (s, 3H), 2.76(m, 4H), 2.30 (m, 1H), 2.09(s, 3H), 1.82 (m, 1H), 1.63 (s, 3H), 1.25 (t, 3H, J=7.6 Hz).

Example 11

[0188] Preparation of Compound 2

[0189] To a stirred solution of Compound 100 (47 mg, 0.12 mmol) inanhydrous tetrahydrofuran (8 mL) at 0° C. was added triethylamine (0.03mL, 0.21 mmol) followed by hydrocinnamoyl chloride (34 mg; 0.20 mmol).The reaction was allowed to stir for 21 hours slowly warming to roomtemperature. The solvent was removed by rotary evaporation and theresidue was treated with ethyl acetate and saturated aqueous sodiumchloride solution. The organic layer was separated, dried over anhydroussodium sulfate, filtered and concentrated. The residue was purified byflash column chromatography on silica gel using 8:1:1 ethyl acetate:dichloromethane:acetonitrile as the eluent to give Compound 2 (45 mg,73%) as a white foam. ¹H NMR (300 MHZ, CDCl₃) δ 8.36 (d, J=3.6 Hz, 1H),8.12 (s, 1H), 7.78 (d, J=8.1 Hz, 2H), 7.53 (d, J=7.8 Hz, 1H), 7.29 (d,J=8.1 Hz, 2), 7.22-7.11 (m, 4H), 7.03-7.00 (m, 2H),6.55 (s, 1H), 6.48(d, J=7.8 Hz, 1H), 5.91 (d, J=9.3 Hz, 1H), 4.85-4.59 (m, 3H), 2.88-2.59(m, 6H), 2.30-2.22 (m, 4H), 1.75-1.67 (m, 1H), 1.25 (t, J=7.8 Hz, 3H)¹³C NMR (75 MHZ, CDCl₃) δ 172.2, 149.7, 148.5, 144.5, 142.9, 141.0,140.4, 138.6, 137.0, 133.1, 128.7, 128.6, 128.41, 128.35, 127.2, 126.27125.8, 124.1, 123.7, 58.3, 50.4, 36.0, 34.7, 31.7, 29.7, 28.8, 15.2.

Example 12

[0190] Preparation of Compound 49

[0191] To a stirred solution of Compound 103 (49 mg, 0.13 mmol) inanhydrous tetrahydrofuran (1 mL) at room temperature were addedtriethylamine (0.028 mL, 0.20 mmol) and hydrocinnamoyl chloride (0.024mL, 0.16 mmol). After 24 hours, additional triethylamine (0.028 mL, 0.20mmol) and hydrocinnamoyl chloride (0.024 mL, 0.16 mmol) were added andthe reaction mixture was allowed to stir an additional 24 hours. Thereaction was diluted with ethyl acetate and the organic layer was washedwith saturated aqueous sodium bicarbonate solution, water, and saturatedaqueous sodium chloride solution. The organic was concentrated and theresidue was purified by flash column chromatography on silica gel using2:1 hexanes:ethyl acetate as the eluent to give Compound 49 (40 mg, 58%)as a colorless oil.

[0192]¹H NMR (300 MHZ, CDCl₃) δ (ppm): 8.63 (2H, d, J=4.9 Hz), 7.81 (2H,d, J=8.3 Hz), 7.31-7.17 (8H, m), 7.09 (1H, t, J=4.7 Hz), 7.01 (1H, dd,J=1.7, 7.9 Hz), 6.91 (1H, s), 5.02 (1H, d, J=9 Hz), 4.82 (1H, q, J=8.0Hz), 3.06-2.63 (6H, m), 2.71 (2H, q, J=7.5 Hz), 2.35-2.25 (1H, m),1.78-1.71 (1H, m), 1.26 (3H, t, J=7.5 Hz).

[0193]¹³C NMR (75 MHZ, CDCl₃) δ (Ppm): 174.14, 161.34, 158.39, 143.61,142.62, 141.15, 139.95, 138.31, 128.78, 128.68, 128.59, 128.51, 128.34,127.27, 126.21, 125.76, 124.34, 117.69, 58.60, 38.67, 35.04, 31.63,29.86, 28.85, 15.17.

[0194] BioAssays

[0195] The cloning, construction and testing of CHO cells that expresshuman voltage-gated potassium channels are described in prior U.S.patent application Ser. No. 08/893,160 (published as WO 98/04521), asare assays measuring ⁸⁶rubidium efflux from cell monolayers;fluorescence measurement of cell membrane potential;electrophysiological studies and lymphocyte proliferation studies.

[0196] The efficacy of various compounds of the present invention asinhibitors of Kv1.5 are shown in Table 1 (using the known patch clamptechniques cited above and described in detail in WO 98/04521, thedisclosure of which is incorporated herein by reference. TABLE 1 %Inhibition Compound at 0.1 μM (n2) 2 55 4 50 10 53 33 59 37 53 46 35 4966 75 48 86 55 93 33 94 53 148 58 154 37 157 40

[0197] The principles, preferred embodiments and modes of operation ofthe present invention have been described in the foregoingspecification. The invention which is intended to be protected herein,however, is not to be construed as limited to the particular formsdisclosed, since they are to be regarded as illustrative rather thanrestrictive. Variations and changes may be made by those skilled in theart without departing from the spirit of the invention. Those skilled inthe art will recognize variations in the processes as described aboveand will recognize appropriate modifications based on the abovedisclosure for making and using the compounds of the invention.

[0198] In the forgoing specification, the following abbreviations areused: Designation Reagent or Fragment m-CPBA meta-chloroperoxybenzoicacid Me methyl Et ethyl NaBH₄ sodium borohydride CH₂Cl₂ dichloromethaneSnCl₂ tin (II) chloride dihydrate CDCl₃ chloroform-d

We claim:
 1. A compound having potassium channel inhibitory activity offormula (I), or a pharmaceutically acceptable salt or prodrug thereof:

wherein, A, B, and D are selected from a substituted carbon atom, anitrogen atom or N→O, wherein at least one of A, B, and D is asubstituted carbon atom and at most only one of A, B and D is N→O; E andG are each hydrogen, or E and G taken together form a bond; R¹ isselected from hydrogen, alkyl, carbocycloalkyl, aryl, heterocyclo,heteroaryl, alkoxy, aryloxy, and substituted amino; Y is selected from abond, alkyl, carbocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, andheterocyclo; X is one of C═O, C═S or SO₂; R² and R³ are independentlyselected from hydrogen (H), alkyl, carbocycloalkyl, aryl, (aryl)alkyl,heterocyclo, (heterocyclo)alkyl, heteroaryl, (heteroaryl)alkyl,aminoalkyl; substituted aminoalkyl, carboxyalkyl, alkoxyalkanoyl,aminoalkanoyl, substituted aminoalkanoyl, alkanoylamidoalkyl,alkanoyl(substituted amido)alkyl, aroylamidoalkyl, aroyl(substitutedamido)alkyl, heterocyclocarbonylamidoalkyl,heterocyclocarbonyl(substituted amido)alkyl, heteroaroylamidoalkyl, andheteroaroyl(substituted amido)alkyl; R⁴ is selected from alkyl,carbocycloalkyl, aryl, (aryl)alkyl, heteroaryl and heterocyclo; R⁵ andR⁶ are each independently selected from hydrogen and alkyl; R⁷ isindependently selected from hydrogen, alkyl, hydroxy, alkoxy, amino,substituted amino, nitro, cyano, halo, carboxy, alkoxycarbonyl,aminocarbonyl, substituted aminocarbonyl and n is 1, 2 or 3; Z isselected from hydrogen, alkyl, hydroxy, SH, alkoxy, aryloxy, alkylthio,amino, substituted amino, alkoxycarbonyl, alkanoylamido, aroylamido,heterocyclocarbonylamido, heteroaroylamido, alkanoyl(alkylsubstituted)amido, aroyl(alkylsubstituted)amido, heteroaroyl(alkylsubstituted)amido,and heterocyclocarbonyl(alkyl substituted)amido; with the provisos thati) when R⁴ is aryl, then R⁴ is not a 3,4-dialkoxy phenyl, or a3-cycloalkylalkoxy, 4-alkoxy phenyl and ii) when A, 13, and D are allCH, and Z is H, OR^(a), or NR^(b)R^(c) wherein R^(a) is one of H,(CH₂)_(m)—R⁸ or C(O)—(CH₂)_(m)—R⁸, m is 1 to 5, R⁸ is N(R⁹)₂, N(R⁹)₃L orCO₂R⁹, each R⁹ being independently selected from one of H or alkyl, andL is a counter ion, R^(b) is H or alkyl; R^(c) is H, alkyl, or CO₂R¹⁰,and R¹⁰ is alkyl; then when R² is hydrogen, or methyl, R³ is nothydrogen, or alkyl, and when R³ is H, or alkyl then R² is not H, ormethyl.
 2. A compound having potassium channel inhibitory activity offormula (II), or a pharmaceutically acceptable salt or prodrug thereof

wherein R¹ is selected from hydrogen, alkyl, carbocycloalkyl, aryl,heterocyclo, heteroaryl, alkoxy, aryloxy, and substituted amino; Y isselected from a bond, alkyl, carbocycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, and heterocyclo; X is one of C═O, C═S or SO₂; R² and R³ areindependently selected from hydrogen, alkyl, carbocycloalkyl, aryl,(aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl,(heteroaryl)alkyl, aminoalkyl; substituted aminoalkyl, carboxyalkyl,alkoxyalkanoyl and aminoalkanoyl; R⁴ is selected from alkyl,carbocycloalkyl, aryl, (aryl)alkyl, heteroaryl and heterocyclo; Z isselected from hydrogen, alkyl, hydroxyl, amino and substituted amino;with the provisos that i) when R⁴ is aryl, then R⁴ is not a 3,4-dialkoxyphenyl, or a 3-cycloalkylalkoxy, 4-alkoxy phenyl and ii) when A, B, andD are all CH, and Z is H, OR^(a), or NR^(b)R^(c) wherein R^(a) is one ofH, (CH₂)_(m)—R⁸ or C(O)—(CH₂)_(m)—R⁸, m is 1 to 5, R⁸ is N(R⁹)₂, N(R⁹)₃Lor CO₂R⁹, each R⁹ being independently selected from one of H or alkyl,and L is a counter ion, R^(b) is H or alkyl; R^(c) is H, alkyl, orCO₂R¹⁰, and R¹⁰ is alkyl; then when R² is hydrogen, or methyl, R³ is nothydrogen, or alkyl, and when R³ is H, or alkyl then R² is not H, ormethyl.
 3. A compound having potassium channel inhibitory activity offormula (III), or a pharmaceutically acceptable salt or prodrug thereof:

wherein, A, B, and D are substituted carbon atoms, or one of A, B, and Dis a nitrogen atom, or N→O; E and G are each hydrogen, or E and G takentogether form a bond; R¹ is selected from hydrogen, alkyl,carbocycloalkyl, aryl, heterocyclo, heteroaryl, alkoxy, aryloxy, andsubstituted amino; Y is selected from a bond, alkyl, carbocycloalkyl,alkenyl, alkynyl, aryl, heteroaryl, and heterocyclo; X is one of C═O,C═S or SO₂; R² and R³ are independently selected from hydrogen, alkyl,carbocycloalkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl,heteroaryl, (heteroaryl)alkyl, aminoalkyl; substituted aminoalkyl,carboxyalkyl, alkoxyalkanoyl and aminoalkanoyl; R⁴ is selected fromalkyl, carbocycloalkyl, aryl, (aryl)alkyl, heteroaryl and heterocyclo;R⁵ and R⁶ are each independently selected from hydrogen and alkyl; R⁷ isindependently selected from hydrogen, alkyl, hydroxy, alkoxy, amino,substituted amino, nitro, cyano, halo, carboxy, alkoxycarbonyl,aminocarbonyl, substituted aminocarbonyl and n is 1, 2 or 3; Z isselected from hydrogen, alkyl, hydroxy, SH, alkoxy, aryloxy, alkylthio,amino, substituted amino, alkoxyalkanoyl, alkanoylamido, aroylamido,heteroaroylamido, heterocyclocarbonylamido,alkanoyl(alkylsubstituted)amido, aroyl(alkylsubstituted)amido,heteroaroyl(alkylsubstituted)amido andheterocyclocarbonyl(alkylsubstituted)amido; with the provisos that i)when R⁴ is aryl, then R⁴ is not a 3,4-dialkoxy phenyl, or a3-cycloalkylalkoxy, 4-alkoxy phenyl and ii) when A, B, and D are all CH,and Z is H, OR^(a), or NR^(b)R^(c) wherein R^(a) is one of H,(CH₂)_(m)—R⁸ or C(O)—(CH₂)_(m)—R⁸, m is 1 to 5, R⁸ is N(R⁹)₂, N(R⁹)₃L orCO₂R⁹, each R⁹ being independently selected from one of H or alkyl, andL is a counter ion, R^(b) is H or alkyl; R^(c) is H, alkyl, or CO₂R¹⁰,and R¹⁰ is alkyl; then when R² is hydrogen, or methyl, R³ is nothydrogen, or alkyl, and when R³ is H, or alkyl then R² is not H, ormethyl.
 4. A compound having potassium channel inhibitory activity offormula (IV), or a pharmaceutically acceptable salt or prodrug thereof:

wherein A, B, and D are all CH, or one of A, B, and D is a nitrogen atomor N→O; R¹ is selected from hydrogen, alkyl, carbocycloalkyl, aryl,heterocyclo, heteroaryl, alkoxy, aryloxy and substituted amino; Y isselected from a bond, alkyl, carbocycloalkyl, alkenyl, alkynyl, aryl,heteroaryl and heterocyclo; R² and R³ are independently selected fromhydrogen, alkyl, carbocycloalkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyclo)alkyl, heteroaryl, (heteroaryl)alkyl, aminoalkyl;substituted aminoalkyl, carboxyalkyl, alkoxyalkanoyl and aminoalkanoyl;R⁴ is selected from aryl, heteroaryl and heterocyclo; Z is selected fromhydrogen, alkyl, hydroxy, SH, alkoxy, aryloxy, alkylthio, amino,substituted amino, alkoxyalkanoyl, alkanoylamido, aroylamido,heteroaroylamido, heterocyclocarbonylamido,alkanoyl(alkylsubstituted)amido, aroyl(alkylsubstituted)amido,heteroaroyl(alkylsubstituted)amido andheterocyclocarbonyl(alkylsubstituted)amido; with the provisos that i)when R⁴ is aryl, then R⁴ is not a 3,4-dialkoxy phenyl, or a3-cycloalkylalkoxy, 4-alkoxy phenyl and ii) when A, B, and D are all CH,and Z is H, OR^(a), or NR^(b)R^(c) wherein R^(a) is one of H,(CH₂)_(m)—R⁸ or C(O)—(CH₂)_(m)—R⁸, m is 1 to 5, R⁸ is N(R⁹)₂, N(R⁹)₃L orCO₂R⁹, each R⁹ being independently selected from one of H or alkyl, andL is a counter ion, R^(b) is H or alkyl; R^(c) is H, alkyl, or CO₂R¹⁰,and R¹⁰ is alkyl; then when R² is hydrogen, or methyl, R³ is nothydrogen, or alkyl, and when R³ is H, or alkyl then R² is not H, ormethyl.
 5. A compound having potassium channel inhibitory activity offormula (V), or a pharmaceutically acceptable salt or prodrug thereof:

R¹ is selected from hydrogen, alkyl, carbocycloalkyl, aryl, heterocyclo,heteroaryl, alkoxy, aryloxy and substituted amino; Y is selected from asingle bond, alkyl, carbocycloalkyl, aryl, heteroaryl and heterocyclo;R² is selected from aryl, aralkyl, heterocyclo, (heterocyclo)alkyl,heteroaryl and heteroaralkyl; R³ is selected from hydrogen, alkyl, aryl,aralkyl, heteroaryl and heteroaralkyl; R⁴ is selected from aryl,heteroaryl and heterocyclo; Z is selected from hydrogen and hydroxyl;with the provisos that when R⁴ is aryl, then R⁴ is not a 3,4-dialkoxyphenyl, or a 3-cycloalkylalkoxy, 4-alkoxy phenyl.
 6. The compound ofclaim 1, or a pharmaceutically acceptable salt or prodrug thereof,wherein X is C═O.
 7. A pharmaceutical composition comprising thecompound of claim 1, or a pharmaceutically acceptable salt or prodrugthereof and a pharmaceutically acceptable diluent or carrier.
 8. Apharmaceutical composition comprising the compound of claim 2, or apharmaceutically acceptable salt or prodrug thereof and apharmaceutically acceptable diluent or carrier.
 9. A pharmaceuticalcomposition comprising the compound of claim 3, or a pharmaceuticallyacceptable salt or prodrug thereof and a pharmaceutically acceptablediluent or carrier.
 10. A pharmaceutical composition comprising thecompound of claim 4, or a pharmaceutically acceptable salt or prodrugthereof and a pharmaceutically acceptable diluent or carrier.
 11. Apharmaceutical composition comprising the compound of claim 5, or apharmaceutically acceptable salt or prodrug thereof and apharmaceutically acceptable diluent or carrier.
 12. A pharmaceuticalcomposition comprising the compound of claim 6, or a pharmaceuticallyacceptable salt or prodrug thereof and a pharmaceutically acceptablediluent or carrier.
 13. A method for inhibiting potassium transportacross cellular membranes possessing potassium channels comprisingexposing a cell membrane possessing said channels to the presence of thecompound of claim 1, or a pharmaceutically acceptable salt or prodrugthereof.
 14. The method of claim 13 wherein the potassium channel is avoltage gated potassium channel.
 15. The method of claim 14 wherein thepotassium channel is selected from a potassium channel responsible forcardiac I_(Kur) potassium current, a potassium channel responsible forT-lymphocyte I_(Kn) potassium current and potassium channels containingone of Kv1.5 or Kv1.3 α-subunit gene products.
 16. A method forinhibiting potassium transport across cellular membranes possessingpotassium channels comprising exposing a cell membrane possessing saidchannels to the presence of the compound of claim 2, or apharmaceutically acceptable salt or prodrug thereof.
 17. The method ofclaim 16 wherein the potassium channel is a voltage gated potassiumchannel.
 18. The method of claim 17 wherein the potassium channel isselected from a potassium channel responsible for cardiac I_(Kur)potassium current, a potassium channel responsible for T-lymphocyteI_(Kn) potassium current and potassium channels containing one of Kv1.5or Kv1.3 α-subunit gene products.
 19. A method for inhibiting potassiumtransport across cellular membranes possessing potassium channelscomprising exposing a cell membrane possessing said channels to thepresence of the compound of claim 3, or a pharmaceutically acceptablesalt or prodrug thereof.
 20. The method of claim 19 wherein thepotassium channel is a voltage gated potassium channel.
 21. The methodof claim 20 wherein the potassium channel is selected from a potassiumchannel responsible for cardiac I_(Kur) potassium current, a potassiumchannel responsible for T-lymphocyte I_(Kn) potassium current andpotassium channels containing one of Kv1.5 or Kv1.3 α-subunit geneproducts.
 22. A method for treating cardiac arrhythmias which comprisesadministering to a patient in need thereof, a pharmaceutically effectiveamount of the compound of claim 1, or a pharmaceutically acceptable saltor prodrug thereof.
 23. A method for treating a cell proliferativedisorder which comprises administering to a patient in need thereof, apharmaceutically effective amount of the compound of claim 1, or apharmaceutically acceptable salt or prodrug thereof.
 24. A method fortreating cardiac arrhythmias which comprises administering to a patientin need thereof, a pharmaceutically effective amount of the compound ofclaim 2, or a pharmaceutically acceptable salt or prodrug thereof.
 25. Amethod for treating a cell proliferative disorder which comprisesadministering to a patient in need thereof, a pharmaceutically effectiveamount of the compound of claim 2, or a pharmaceutically acceptable saltor prodrug thereof.
 26. A method for treating cardiac arrhythmias whichcomprises administering to a patient in need thereof, a pharmaceuticallyeffective amount of the compound of claim 3, or a pharmaceuticallyacceptable salt or prodrug thereof.
 27. A method for treating a cellproliferative disorder which comprises administering to a patient inneed thereof, a pharmaceutically effective amount of the compound ofclaim 3, or a pharmaceutically acceptable salt or prodrug thereof.
 28. Amethod for treating cardiac arrhythmias which comprises administering toa patient in need thereof, a pharmaceutically effective amount of thecompound of claim 4, or a pharmaceutically acceptable salt or prodrugthereof.
 29. A method for treating cardiac arrhythmias which comprisesadministering to a patient in need thereof, a pharmaceutically effectiveamount of the compound of claim 5, or a pharmaceutically acceptable saltor prodrug thereof.
 30. A method for treating cardiac arrhythmias whichcomprises administering to a patient in need thereof, a pharmaceuticallyeffective amount of the compound of claim 6, or a pharmaceuticallyacceptable salt or prodrug thereof.